1. Field of the Invention
The present invention relates to a marker and reagent for detecting human IL-17-producing helper T-cells (hereinafter also referred to as “Th17 cells”) and a method for detecting human Th17 cells.
2. Description of the Related Art
Rheumatoid arthritis (hereinafter referred to as “RA”) is the systemic inflammatory autoimmune disease whose main clinical symptom is arthritis. The state of RA is diagnosed by rational symptoms such as joint pain or by visual procedures such as the observations on the extent of swelling or bone X-ray. However, no quantitative index has been established. Thus, no quantitative method for continuously monitoring the treatment effects has been established under the current state of the art.
The pathogenesis of RA has not been elucidated. It is considered that bacterial infections and the like trigger an inflammation in joint tissues via complicated networks of immunocytes and cytokines.
Helper T-cells play a central role in immune reactions. Immature helper T-cells (naïve T-cells) are differentiated into helper T-cells when an antigen is presented by antigen-presenting cells. When specific cytokines are present at this time, naïve T-cells are differentiated into four types of the cells, which are helper T-cells producing interferon (IFN)-γ (Th1 cells), helper T-cells producing interleukin (IL)-4 (Th2 cells), helper T-cells producing IL-17 (Th17 cells) and regulatory T-cells having immunosuppressive effects (Treg cells).
It has been shown that among these helper T-cells, Th17 cells can be involved in the onset of RA.
It has been suggested that IL-17 is deeply involved in the formation of pathological conditions and in particular joint and bone deformities because the level of IL-17 is significantly higher in synovial fluid of RA patients than in that of the patients of osteoarthritis and T-cells in synovial tissue from RA patients include IL-17 positive cells (see Japanese Unexamined Patent Publication No. 2000-186046). Japanese Unexamined Patent Publication No. 2000-186046 also discloses that IL-17 can be used as a diagnostic marker of RA.
Japanese Unexamined Patent Publication No. 2007-506100 discloses that the analysis of cytokines in peripheral blood serum of RA patients revealed that the levels of IFN-γ, IL-1β, TNF-α, G-CSF, GM-CSF, IL-6, IL-4, IL-10, IL-13, IL-5 and IL-7 were significantly high and the levels of IL-2, CXCL8/IL-8, IL-12 and CCL2/MCP-1 were not high in RA patients.
According to the studies by Ivanov et al. (“The Orphan Nuclear Receptor RORγt Directs the Differentiation Program of Proinflammatory IL-17+ T Helper Cells”, Cell, 2006, 126, p. 1121-1133), Stumhofer et al. (“Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system”, Nature Immunology, 2006, vol. 7, p. 937-945), and Wilson et al. (“Development, cytokine profile and function of human interleukin 17-producing helper T cells”, Nature Immunology, 2007, vol. 8, p. 950-95′7), the following facts have been shown about Th17 cells:                a nuclear receptor called RORγt has an important role in the differentiation of Th17 cells;        IL-6, IL-23 and TGF-β induce the differentiation of immature helper T-cells (naïve T-cells) to Th17 cells;        they express IL-17A, IL-17F, IL-6, IL-22, IL-26, TNF, IFN-γ and CCL20; and        IL-23 receptor and IL-12 receptor β are located on the surface of Th17 cells.        